PROJECT SUMMARY Recent advances in genome sciences have allowed for early applications of precision medicine. While the genes causing over 4,000 Mendelian diseases have been identified, many leading to new diagnostics and therapeutics, most diseases prove more complicated. For over a decade, researchers have looked for genetic variation that is linked to these more complex diseases through genome wide association studies. While this avenue of research has generated over 18,000 unique variants linked to disease, the interpretation of these variants, and therefore their application to clinical medicine, remains unresolved. Recently, several groups have identified that many of these variants overlap enhancer elements, regions of DNA responsible for the spatiotemporal expression of genes. In this proposal, I aim to functionally validate and interpret the roles of thousands of these variants in complex disease. To do so, I am developing novel technologies with broad application to genome sciences and proteomics. I am developing methods to generate complex libraries of DNA to test, in which I can program specific variation. This same technology has been adopted by others to design proteins with novel functions. I am also developing a novel assay to test the effects of thousands of these variants on enhancer function with unprecedented sequence and chromosomal context. Together, these methods permit the simultaneous analysis of thousands of predefined enhancer variants. This study will provide insight into the genetic basis of complex traits and may guide the development of novel diagnostics and therapeutics.